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Research ArticleArticle

Cyclosporine A- and Tacrolimus-Mediated Inhibition of CYP3A4 and CYP3A5 In Vitro

Rune Amundsen, Anders Åsberg, Ingrid Kristine Ohm and Hege Christensen
Drug Metabolism and Disposition April 2012, 40 (4) 655-661; DOI: https://doi.org/10.1124/dmd.111.043018
Rune Amundsen
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Anders Åsberg
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Ingrid Kristine Ohm
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Hege Christensen
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Abstract

Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (Ki) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC50 after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.043018.

  • ABBREVIATIONS:

    CNI
    calcineurin inhibitors
    CsA
    cyclosporine A
    Tac
    tacrolimus
    HLM
    human liver microsomes
    MDZ
    midazolam
    LC-MS
    liquid chromatography-mass spectrometry
    AUC
    area under the concentration versus time curve
    P450
    cytochrome P450.

  • Received September 28, 2011.
  • Accepted December 28, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Research ArticleArticle

CYCLOSPORINE A- AND TACROLIMUS-MEDIATED INHIBITION OF CYP3A

Rune Amundsen, Anders Åsberg, Ingrid Kristine Ohm and Hege Christensen
Drug Metabolism and Disposition April 1, 2012, 40 (4) 655-661; DOI: https://doi.org/10.1124/dmd.111.043018

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Research ArticleArticle

CYCLOSPORINE A- AND TACROLIMUS-MEDIATED INHIBITION OF CYP3A

Rune Amundsen, Anders Åsberg, Ingrid Kristine Ohm and Hege Christensen
Drug Metabolism and Disposition April 1, 2012, 40 (4) 655-661; DOI: https://doi.org/10.1124/dmd.111.043018
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